P683: TRIALS IN PROGRESS: FIRST-IN-HUMAN STUDY OF ELVN-001, A SELECTIVE BCR::ABL1 TYROSINE KINASE INHIBITOR, IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA WHO FAILED PREVIOUS TYROSINE KINASE INHIBITOR THERAPIES
Authors: Fabian Lang, Susan Branford, Joseph P. Lyssikatos, Helen Collins, Andreas Hochhaus
Journal: HemaSphere (2023)

Background: Despite the benefits BCR::ABL1 tyrosine kinase inhibitors (TKIs) have provided altering the natural history of chronic myeloid leukemia (CML), resistance/lack of response and intolerability occurs. ELVN-001 is a highly selective small molecule active site inhibitor of ABL1 that does not significantly inhibit the receptor tyrosine kinases PDGFR, KIT, VEGFR2 or the Src-family (eg SRC, LCK, LYN, FYN). In vitro data also supports ELVN-001 targeting the most common BCR::ABL1 mutation, T315I and not being a substrate for drug efflux transporters such as BCRP, which may contribute to resistance or sensitivity to other TKIs. Ba/F3 cells expressing a range of the most prevalent on-target BCR::ABL1 resistance mutants indicated that with the exception of certain P-loop mutations and F317L, ELVN-001 maintained potency, including for the myristoyl pocket mutations A344P and P465S and was active against the M244V mutation, an ATP pocket mutation known to confer resistance to asciminib. Non-clinical data suggests ELVN-001 has a favorable absorption, distribution, metabolism, elimination and a pharmacokinetic (PK) profile supporting once daily (QD) dosing, low risk of QTc prolongation, and potential to avoid drug-drug interactions, particularly CYP-mediated. This first-in-human (FIH) study will evaluate the safety, tolerability, PK and preliminary anti-CML activity of ELVN-001 in patients (pts) with chronic phase (CP) CML with and without T315I mutations. Aims: The primary objectives are to determine the recommended doses for expansion (RDE) and to evaluate the safety and tolerability of ELVN-001. Secondary objectives are to assess the PK profile and preliminary efficacy. Methods: A phase 1 open-label, multi-center, dose escalation and expansion study. Eligible pts are adults with CP-CML who are intolerant or have failed (as per ELN 2020 Recommendations) available TKIs known to be active for treatment of their CML. Other key eligibility criteria are Eastern Cooperative Oncology Group performance status 0–2, adequate bone marrow, renal, and liver function, and resolved adverse effects of prior therapy. Prior stem cell transplant is allowed. Successive cohorts will receive escalating doses of ELVN-001 starting at 10 mg QD. Dosing will be continuous in 28-day cycles until treatment failure, disease progression or unacceptable toxicity. A standard 3 + 3 dose escalation will be used, with PK/pharmacodynamic modeling to identify the RDEs, assuming toxicity is not dose limiting. Up to an additional 30 patients may be enrolled across one or more dose levels (a maximum of 10 additional patients at a specific dose level) to confirm evidence of anti-CML activity and provide confidence in PK variability prior to opening Phase 1b for enrollment. In Phase 1b Safety and efficacy of ELVN-001 will be further explored in CP-CML without T315I mutations and 1a cohort of T315I mutated CP-CML. Mutational analyses by Sanger and NGS will be conducted at baseline and end of treatment. Results: Primary endpoints are dose limiting toxicities, adverse events, laboratory and ECG abnormalities. Secondary endpoints are PK parameters, response based on BCR::ABL1 transcript levels by quantitative RT-PCR and hematology. Summary/Conclusion: This FIH study will evaluate dosing, safety, tolerability, PK profile, and preliminary efficacy of ELVN-001 in CP-CML with and without T315I mutation. Study sponsor: Enliven Therapeutics. NCT05304377 Keywords: BCR::ABL, Chronic myeloid leukemia, Tyrosine kinase inhibitor, Phase I